Abstract
Epidermal growth factor receptor (EGFR) inhibitors have limited efficacy in head and neck squamous cell carcinoma (HNSCC) due to various resistance mechanisms, such as activation of the insulin-like growth factor-1 receptor (IGF1R), which initiates pro-survival signaling. Survivin, a member of the inhibitor of apoptosis proteins family, is expressed at relatively high levels in malignant tissues and plays a role in cell division. Expression of survivin in tumors has been shown to correlate with poor prognosis due to chemotherapy resistance and anti-apoptotic behavior. We previously demonstrated that activation of the IGF1R reduces sensitivity to EGFR-tyrosine kinase inhibitors (TKIs) via reduced apoptosis suggesting a role of survivin in this process. This study evaluates the role of survivin in IGF1R-mediated lapatinib resistance. Using HNSCC cell lines FaDu and SCC25, survivin expression increased and lapatinib sensitivity decreased with IGF1R activation. Further, these effects were reversed by the survivin inhibitor YM-155. Conversely, survivin expression and lapatinib sensitivity were unchanged with IGF1R activation in UNC10 cells. YM-155 enhanced the inhibitory effect of lapatinib on UNC10 cells, regardless of activation of the IGF1R. These results demonstrate that enhanced survivin expression correlates with IGF1R-mediated lapatinib resistance in HNSCC cells and suggest that regulation of survivin expression may be a key mechanistic element in IGF1R-based therapeutic resistance. Combinatorial treatment with survivin antagonists and EGFR-TKIs warrants further investigation.
Highlights
Head and neck squamous cell carcinoma (HNSCC) constitutes ∼3% of all malignancies with over 50,000 new cases diagnosed in the United States alone [1]
We have previously demonstrated that activation of the insulin-like growth factor-1 receptor (IGF1R) reduces sensitivity to Epidermal growth factor receptor (EGFR)-tyrosine kinase inhibitors (TKIs) in HNSCC cell lines via reduced apoptosis [3, 15]
In resistant UNC10 cells, basal survivin expression is high and shows limited reduction in response to lapatinib treatment. This suggests the possibility that survivin expression may be a predictive marker of lapatinib sensitivity, and perhaps sensitivity to other EGFR-TKIs
Summary
Head and neck squamous cell carcinoma (HNSCC) constitutes ∼3% of all malignancies with over 50,000 new cases diagnosed in the United States alone [1]. Epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs) have potential as a molecular targeted therapy for HNSCC because more than 90% overexpress the EGFR [3, 4]. Phase II clinical trials with single-agent targeted EGFR inhibitors yielded response rates below 15% despite EGFR expression and inactivation [5, 6]. These findings suggest a compensatory mechanism that promotes cell survival despite EGFR inhibition, resulting in therapeutic resistance. A better understanding of this resistance mechanism has the potential to lead to more effective targeted therapy for HNSCC
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